Post-traumatic osteoarthritis (PTOA) is characterized by degeneration of articular cartilage and subchondral bone, and is commonly a long-term consequence of traumatic joint injury, with approximately 50% of individuals with anterior cruciate ligament (ACL) rupture or meniscectomy developing PTOA within 10-20 years. In our lab we have developed a novel mouse model of knee injury that uses non-invasive mechanical loading to induce rupture of the ACL, creating a joint injury response that is relevant to PTOA in humans. Preliminary studies using this model indicate that there is rapid (within 1 week) and considerable subchondral bone loss following non-invasive knee injury, followed by a rapid partial recovery of bone mass by 4 weeks post-injury. We hypothesize that injury-induced inflammation acts as a mass activation event for bone remodeling, which subsequently drives these substantial short-term bone changes. Inhibiting the injury-induced inflammatory response may effectively stop these short-term structural changes, and may prevent longer-term degeneration of subchondral bone and articular cartilage, however the role of injury-induced inflammation in PTOA development, and the window of opportunity for treatment have not been defined. In this study we will use our novel mouse model of knee injury to determine the time course of PTOA progression, and determine the effect of the injury-induced inflammatory response on PTOA development. In Aim 1 we will determine the specific mechanisms and time course of the injury-induced inflammatory response, and whether this response is associated with the time course of subchondral bone and articular cartilage changes following knee injury. In Aim 2 we will assess the ability of treatments that inhibit the inflammatory cytokines tumor necrosis factor- (TNF-), interleukin-1 (IL-1), and interleukin-6 (IL-6) to prevent structural cartilage and bone changes initiated by non-invasive knee injury. Results from these studies will help establish the window of opportunity for treatments aimed at slowing or preventing the onset of PTOA, and will establish therapeutic targets associated with the injury-induced inflammatory response. This research will greatly expand our understanding of biological processes following joint injuries, and could lead to a fundamental change in the way traumatic joint injuries are treated in human subjects. This mentored career development award will provide me with resources to conduct research and develop professionally under the guidance of my mentoring team. During the mentored period I will successfully transition from the mentored stage of my career to an independent investigator.